(Applicant's Abstract) Bronchial inflammation is a characteristic feature and proposed mechanism for altered airway function in asthma. Because eosinophils (EOS) are often increased in the circulation, airway fluids, and bronchial mucosa of asthmatic patients, and their products can cause features of asthma, this cell is presumed to be a pivotal component of the inflammatory response and altered pulmonary physiology of asthma. However, recent preliminary results, which have been unable to show any significant benefit following administration of anti-interleukin (IL)-5, a cytokine that promotes EOS activity and survival, to asthmatic patients have now caused reappraisal of current concepts of the eosinophil's role in asthma. To address this controversy, antigen provocation has been used as a model to define inflammatory mechanisms in asthma and has shown circulating EOS are primed and then, as they enter the airway, become activated to generate an inflammatory response leading to alterations in pulmonary physiology. As a consequence, we now hypothesize that development of eosinophilic inflammation and a subsequent asthmatic exacerbation is the result of (1) an initial priming, or "first hit," of circulating EOS to promote survival, endothelial adhesion, and migration to the lung; (2) activation, through a "second hit," of primed EOS in the airway by a variety of stimuli, including chemokines/cytokines acting via 7-transmembrane receptors, to release granule proteins; (3) an increased retention of EOS in the airway walls of asthma patients; and (4) that these EOS-generated effects lead to specific preliminary function changes, including increased hyperresponsiveness through neurogenic pathways, and airflow obstruction via airway-parenchymal uncoupling. Moreover, we propose that the initial phase of an acute exacerbation of asthma, i.e. following antigen (AG) exposure or withdrawal of inhaled corticosteroid (ICS), is IL-5 dependent followed by a transition to persistent inflammation, which is IL-5 independent and characterized by a loss of IL-5 receptors on airspace EOS, a shift to granulocyte-macrophage colony stimulating factor (GM-CSF) regulation of EOS function, and a phenotype alteration such that airspace EOS act as antigen presenting cells. To establish this hypothesis and more precisely define a role for EOS in asthma, asthmatic subjects will be selected for study and both AG challenge and withdrawal of ICS will be used to provoke asthmatic symptoms that are predicted to elicit changes in circulating and lung EOS function which can then be analyzed in relationship to altered pulmonary histopathology, physiology and structure to provide a more precise understanding of the role of eosinophilic inflammation in persistent symptoms of asthma.